PROJECT SUMMARY Dysfunction in the ability to inhibit unwanted responses, response inhibition, is a key component of many neuropsychiatric disorders. How the brain resolves response conflict remains unclear, but is thought to rely on several signals including response selection, the detection of conflict and the ability to adapt behavior based on prior experience. Definitions of these constructs ? as we define them ? are as follows: ?Response selection? signals are tied to the motor system and reflect the nature of the response (e.g., move left or right). When response selection signals are in conflict with each other (e.g., when neurons that signal leftward and rightward are simultaneously active), ?conflict detection? signals are thought to report the degree of conflict which in turn allows the development of the correct response selection signal, and activates executive control systems responsible for conflict adaptation. ?Conflict adaptation? refers to the ability to slow behavior after experiencing an error and/ or a high conflict situation. We have shown that neurons in dorsal medial striatum (DMS) strongly encode response selections, while neurons in lateral orbitofrontal cortex (OFC) seem to contribute to conflict adaptation signals. Finally, we have shown that neurons in anterior cingulate cortex (ACC) detect response conflict prior to the stop change reaction time (SCRT; point at which behavior cannot be inhibited), which is critical for the resolution of conflict during ongoing behavior. While many studies have suggested that ACC is important for inhibitory control, few studies have examined whether signals generated by ACC during periods of high conflict have behaviorally significant effects on downstream regions like DMS and OFC. In AIM 1 we propose to investigate whether accurate response selections in DMS rely on the conflict detection signals in ACC. We propose to do this by temporarily silencing neurons in ACC, and examining whether this alters behavior as well as neural activity in the DMS during response conflict. To further assess this circuit, in a separate experiment, we propose to optogenetically stimulate neurons in ACC while recording from neurons in DMS to test whether enhanced conflict detection leads to faster and more accurate response selection. In AIM 2 we propose to investigate the importance of ACC conflict detection in the generation of conflict adaptation signals in OFC. We predict that disruption of conflict detection in ACC will lead to diminished conflict adaptation signaling in OFC, and, in a second experiment, that optogenetic stimulation of neurons in the ACC will improve conflict adaptation signals and enhance behavioral accuracy on high conflict trials. Collectively, these findings will provide a new perspective on the circuitry supporting response inhibition.